The objective of this research is to define the specific roles for IL-7, IL-15, and IL-2 in gastrointestinal ILC3 development and plasticity. Compared to other lymphocytes, the greatest frequency and diversity of ILCs exist in the GI tract. Notably, ILC3, the innate counterparts of TH17, are found during homeostatic conditions at especially high frequencies here. Sustained crosstalk between ILC3 and the microbiota suggest that ILCs may have a role in IBD development, and several investigators have demonstrated that ILC compartments are altered in Chron's disease patients and in mouse models of colitis, with a decrease of IL-22 producing ILC3 and increase of inflammatory IFN? producing ILC1. The mechanisms that lead to ILC3/ILC1 balance in steady state and deregulation during colitis remain incompletely understood, but evidence suggests that these processes are regulated in part by IL-7, IL-15, and IL-2. In the current paradigm of ILC development, ILC classes are thought to diverge in their cytokine requirements, as ILC1 depend on IL-15, while ILC3 are reported to require IL-7. Our preliminary studies in IL-7 receptor deficient (IL-7Ra-/-) mice demonstrate that IL-7 signaling is not strictly required for NKp46- or NKp46+ ILC3 development in the siLP. However, these mice do have alterations in ILC compartments, exhibiting a reduced frequency and total number of NKp46+ ILC3, reduced total number of NKp46- ILC3, and increased frequency and number of ILC1 in the small intestine lamina propria. Furthermore, we find NKp46+ ILC3 are significantly reduced in IL2ra-/- mice compared to IL2ra+/- control. Based on our preliminary data, we challenge the current paradigm of ILC development and hypothesize that IL-7, IL-15, and IL-2 can provide partially redundant survival signals to ILC3, but also have non-redundant roles by modulating development, plasticity, and function. This hypothesis raises important questions that will be addressed in this proposal: 1) How does loss of IL-7 signaling result in an ILC3 defect; 2) What is the role of IL-15 and IL-2 in ILC3 development and plasticity? To determine how IL- 7 regulates ILC3, we will perform experiments in IL7Ra-/- and IL7Ra-/- x Rag1-/- mice. To determine the role of IL-15 and IL-2 in ILC3 development and plasticity, we will perform experiments in IL-2ra-/-, IL-15-/-, and IL7Ra-/- x IL-15-/- mice. The long-term goal of this proposed research is a better understanding of IBD pathogenesis.